Viral infections cause considerable morbidity and mortality worldwide. Viruses induce tissue factor (TF) expression in various cell types and this leads to activation of coagulation as part of the innate immune response. Coagulation proteases activate cells by cleavage of protease-activated receptors (PARs). For instance, the TF:FVIIa:FXa activates PAR2 on a variety of cell types. Besides this, other proteases such as trypsin or tryptase can activate PAR2. Toll-like receptors (TLRs) play a central role in host defense. It has been proposed that TLRs and PARs act as a dual-receptor system to detect pathogens. Viral myocarditis causes up to 20% of sudden death in adults less than 40 years of age. Coxsackievirus B3 (CVB3) is considered to be one of the dominant etiological agents of myocarditis. Influenza A and B virus causes the flu. Influenza virus infects epithelial cells in the lung and in severe cases causes viral pneumonia. The elderly are particularly susceptible to the flu. At present, treatment of myocarditis remains nonspecific and only supportive. Furthermore, optimal IAV treatments are still under development. PAR2 is known to play a major role in multiple inflammatory disorder. In addition, expression and activity of PAR2 activating proteases, such as tryptase and trypsin, has been linked to CVB3 myocarditis and influenza virus infection susceptibility. Recently, we discovered that the PAR2 pathway dampens the innate immune response to CVB3 in mice leading to more pronounced myocarditis. Furthermore, we and others found that PAR2 deficiency was associated with reduced influenza virus infection. At present little is known about the underlying pathologic mechanism of PAR2 in CVB3-induced myocarditis and influenza virus infection. The proposal will elucidate the mechanisms by which PAR2 enhances viral infection using mouse models of CVB3 myocarditis and H1N1 influenza A virus infection. More important, we will test a therapeutic approach by inhibiting FXa or PAR2 to improve the outcome after CVB3 or H1N1 infection. The proposed studies are highly significant because they may elucidate new pathways and treatments to treat viral myocarditis, H1N1 influenza A virus infection and viral infections in general.